Recent data has demonstrated that sensory nerves have the capacity to act in an efferent manner. This efferent function is mediated by the release of neuropeptides, such as CGRP and substance P (SP). Despite the observation that CGRP and SP are potent vasodilators, their role in the long-term regulation of cardiovascular function and hypertension is unknown. Recent evidence, largely generated in our laboratory shows that; 1) neuronal expression and/or vascular reactivity to CGRP and SP is increased in experimental hypertension, 2) CGRP and SP receptor blockade significantly increases the BP in several models of experimental hypertension, 3) CGRP KO mice have higher basal BP, lower coronary flow, and greater ischemic cardiac injury; and 4) CGRP KO mice have greater cardiac and renal injury secondary to DOC-salt hypertension. These observations have led to a central hypothesis that states that the sensory nervous system, through the actions of CGRP and SP plays a major role in the long-term modulation of cardiovascular function and the pathophysiology of hypertension. To test this hypothesis, we will determine whether decreased CGRP or SP function (by studying CGRP KO and SP receptor (NK1) KO mice) alters the ability of the sensory nervous system to modulate BP in the absence or presence of hypertension induced by DOC-salt and subtotal-nephrectomy (SN)-salt. These mice will also be subjected to neuronal release of neuropeptides from sensory nerves by capsaicin. In vivo changes in BP in response to specific receptor antagonists of these peptides, systemic and regional hemodynamics (via microspheres), and cardiac function (via Doppler echocardiography) will also be determined. In addition we will determine whether a- CGRP KO or NK-1 KO mice have reduced coronary flows and increased myocardial damage following ischemia/reperfusion injury. This will be accomplished in vitro by studying isolated-perfused hearts from a- CGRP KO mice and NK-1 KO mice. Finally, we will determine whether a-CGRP KO and NK-1 KO mice have greater cardiac and renal injury, independent of BP, secondary to DOC-salt hypertension. Studies investigating the mechanism (ie oxidative stress) of this enhanced tissue injury will also be performed. Taken together, these studies will use a novel experimental paradigm to define the role of the sensory nervous system, through CGRP and SP, in the long-term regulation of cardiovascular function, including the pathogenesis of hypertension.